Erectile dysfunction profoundly impacts the quality of life of 10 to 30 million American men. The NIH Consensus Development Conference on Impotence (December, 1992) considered erectile dysfunction as an important public health problem and pointed to the need for basic research on the biochemical and physiological mechanisms that underlie etiology, pathogenesis and response to treatment of erectile dysfunction. Over the past ten years, considerable progress has been made towards understanding the epidemiological, neuropharmacological and therapeutic aspects of erectile dysfunction. Although pharmacologic intervention via self- intracavernosal injection of vasoactive agents restores erectile function in many patients, this therapeutic approach remains widely unaccepted. The desire and expectation by patients to seek pharmacological (non-invasive) treatment, especially oral medications, requires the development of innovative approaches and strategies that enable effective manipulations of trabecular smooth muscle tone by oral medications. To achieve this goal, a more detailed understanding of penile smooth muscle neuromodulation at the biochemical and molecular levels is necessary. The studies proposed here will focus on the biochemical mechanisms and functional role of a1-adrenergic and muscarinic receptor subtypes in the local control of trabecular smooth muscle tone. The specific aims are: 1) to determine the functional role of a1-adrenergic receptor subtypes (a1-AR) in modulating corpus cavernosum smooth muscle tone; 2) to determine the functional role of muscarinic acetylcholine receptor (mAChR) subtypes in regulation of corpus cavernosum smooth muscle tone; and 3) to determine the regulation of expression of mAChR and a1A, a1B and A1C-AR subtypes in corpus cavernosum smooth muscle by androgens, neurotransmitters, and vasoactive agents. The long term objective is to delineate the biochemical basis of neurotransmitter-receptor function and the interplay (regulation) between adrenergic, cholinergic and non-adrenergic noncholinergic signals in modulating trabecular smooth muscle tone.